ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000018.9) (NC_000018.10)
Evidence for haploinsufficiency phenotype
PubMed ID Description
23383720 Bainbridge et al (2013) identified de novo truncating mutations of ASXL3 in four unrelated individuals with Bohring-Opitz syndrome-like clinical features. All four de novo mutations (two nonsense; one 4 bp deletion; and one 1 bp insertion) detected by whole exome / whole genome sequencing were predicted to result in nonsense-mediated decay or truncated protein. No deleterious ASXL3 mutation was detected in a small cohort of patients with Bohring-Opitz syndrome without causative ASXL1 mutation, consistent with ASXL3 mutations caused a different clinical entity, Bainbridge-Ropers syndrome. However, the authors identified four additional truncating mutations in ASXL3 in reportedly phenotypically normal individuals from large-scale datasets (Thousand Genomes, dbSNP, ESP5400, and Cohorts for Heart and Aging Research in Genomic Epidemiology). These potentially benign variants are located 5? and 3? of the disease-causing mutation hotspot within the first half of the penultimate exon11 (Figure 2). Functional studies were not performed in this study. However, authors stated that truncating ASXL3 mutations are uncommon, and their de novo nature makes it even less likely that they identified these individuals by chance.
26647312 Srivastava et al (2016) identified three novel de novo heterozygous truncating variants in unrelated individuals with Bainbridge-Ropers syndrome using clinical exome sequencing. These mutations (two nonsense and 1 bp insertion) were distributed across ASXL3, outside the original mutation hotspot previously described in exon 11 and instead localize to the 5? end of exon 12 (Figure 1E). The authors showed that the mutated allele mRNA transcripts obtained from primary skin fibroblasts from the mutated allele of a patient were prone to nonsense-mediated decay, and expression of ASXL3 was reduced consistent with loss-of-function mutations. Authors stated that previously described ASXL3 nonsense variants detected in normal individuals may represent mutations arising post-zygotically or during later embryogenesis and thus may be explained by the timing of these de novo mutational events and mosaicism.
27901041 Kuechler et al (2017) described six unrelated individuals with Bainbridge-Ropers syndrome with novel heterozygous de novo loss-of-function variants (3 nonsense; one 1 bp deletion; and two 2 bp deletions) in ASXL3 using whole exome sequencing. All mutations are located in exons 11 and 12 that represent 84% of the entire ASXL3 protein-coding region (Figure 2). Functional studies were not performed in this study

Haploinsufficiency phenotype comments:

Heterozygous de novo loss-of-function mutations in Additional sex combs-like 3 (ASXL3) are associated with Bainbridge-Ropers syndrome (OMIM# 615485) that phenotypically overlaps with Bohring-Opitz syndrome (OMIM# 605039). De novo heterozygous nonsense mutations in ASXL1 have been shown to account for approximately 50% of cases with Bohring-Opitz syndrome (PMID: 21706002). Bainbridge?Ropers syndrome is characterized by failure to thrive, muscular hypotonia, global developmental delay, varying degrees of intellectual disability, profound speech delay, feeding problems, and dysmorphic features. However, the most pervasive characteristics are non-specific features. The haploinsufficiency of ASXL3 caused by genomic copy-number variations (CNVs) has not been reported yet in individuals with Bainbridge?Ropers syndrome or other clinical features. Haploinsufficiency score of 13.78 and the Exome Aggregation Consortium (ExAC) pLI score of 1.00 of ASXL3 support haploinsufficiency of this gene (; Currently, ExAC has listed only three LoF (nonsense) variants and 671 missense variants in ASXL3. However, ExAC reported two fully overlapping copy number deletions (chr18:30913136-30928944) and one partially overlapping duplication (chr18:31537288-31538387) among 60,706 unrelated individuals in this gene interval (z = -0.20). Additional relevant literature is summarized below: 1) Dinwiddie et al (2013) described a de novo frameshift variant (2 bp deletion) in a patient with global developmental delay, microcephaly, and craniofacial anomalies (PMID: 24044690). 2) Zhu et al (2015) identified a de novo frameshift variant (2 bp deletion) in a patient with intellectual disability, microcephaly, mild to moderate hypotonia, and hypermotoric behavior (Supplemental Table 6) (PMID: 25590979). 3) De Rubeis et al (2014) listed ASXL3 among the autism spectrum disorder (ASD) genes (Table 1). The authors identified three LoF variants, two truncating mutations and one whole-gene deletion in individuals with autism (PMID: 25363760).

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

At this time there is no evidence that supports the triplosensitivity of ASXL3